Methods and Apparatus to Stimulate the Heart

ABSTRACT

A method and apparatus for treatment of hypertension and heart failure by increasing secretion of endogenous atrial hormones by pacing of the heart. Pacing is done during the ventricular refractory period resulting in premature atrial contraction that does not result in ventricular contraction. Pacing results in the atrial wall stress, peripheral vasodilation, ANP secretion. Concomitant reduction of the heart rate is monitored and controlled as needed with backup pacing.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/359,218, filed Mar. 20, 2019 (U.S. Patent Publication No.U52019/0275336, published Sep. 12, 2019), which is a continuation ofU.S. application Ser. No. 15/628,870, filed Jun. 21, 2017, now U.S. Pat.No. 10,252,060, issued Apr. 9, 2019, which is a continuation of U.S.application Ser. No. 15/163,078, filed May 24, 2016, now U.S. Pat. No.9,731,136, issued Aug. 15, 2017, which is a continuation of U.S.application Ser. No. 13/688,978, filed Nov. 29, 2012, now U.S. Pat. No.9,370,661, issued Jun. 21, 2016, which is a continuation of U.S.application Ser. No. 12/555,389, filed Sep. 8, 2009, now U.S. Pat. No.8,340,763, issued Dec. 25, 2012, which claims priority to U.S.Provisional Patent Application No. 61/095,120, filed Sep. 8, 2008, allof which are herein incorporated by reference in their entirety.

BACKGROUND

Implantable devices for cardiac stimulation and pacing therapy aredisclosed for cardiac therapies involving the controlled delivery ofelectrical stimulations to the heart for the treatment of hypertension,congestive heart failure, and an apparatus for delivering such therapieswith the objective of increasing stress of atrial muscle walls, alteringsympathetic and parasympathetic nerve stimulation and causing secretionof hormones such as Atrial Natriuretic Peptide (ANP) by the heart muscleand to cause vasodilatation of blood vessels.

Congestive Heart Failure

Congestive heart failure (CHF) occurs when muscle cells in the heart dieor no longer function properly, causing the heart to lose its ability topump enough blood through the body. Heart failure usually developsgradually, over many years, as the heart becomes less and lessefficient. It can be mild, scarcely affecting an individual's life, orsevere, making even simple activities difficult.

Congestive heart failure (CHF) accounts for over 1 million hospitaladmissions yearly in the United States (U.S.) and is associated with a5-year mortality rate of 40%-50%. In the U.S., CHF is currently the mostcostly cardiovascular disease, with the total estimated direct andindirect costs approaching $56 billion in 1999.

Recent advances in the treatment of CHF with medications, includingangiotensin-converting enzyme (ACE) inhibitors, beta-blockers(Carvedilol, Bisoprolol, Metoprolol), Hydralazine with nitrates, andSpironolactone have resulted in significantly improved survival rates.Although many medications have been clinically beneficial, they fallshort of clinician's expectations and as a result consideration hasturned to procedures and devices as additional and more potent heartfailure therapy.

There has been recent enthusiasm for biventricular pacing (pacing bothpumping chambers of the heart) in congestive heart failure patients. Itis estimated that 30% to 50% of patients with CHF have inter-ventricularconduction defects. These conduction defects lead to a discoordinatedcontraction of the left and right ventricles of an already failing andinefficient heart. When the right ventricle alone is paced with apacemaker, the delayed activation of the left ventricle, can also leadto significant dyssynchrony (delay) in left ventricular contraction andrelaxation.

Because ventricular arrhythmias continue to threaten CHF patients andmany anti-arrhythmic drugs have unacceptable side effects, asophisticated implantable cardioverter-defibrillator (ICD) device hasshown encouraging results. Biventricular pacing in combination with ICDsdemonstrates a trend toward improved survival. Preliminary data inanimals and humans using subthreshold (of the type that does not byitself cause heart muscle to contract) stimulation of the heart muscleto modulate cardiac contractility are encouraging and may furtherenhance the quality of life of CHF patients.

Many patients with CHF are not candidates for biventricular pacing or donot respond to this treatment strategy. This also applies to otherrecent advances and experimental therapies. There is a long felt needfor new and better CHF therapies that will improve and prolong the lifeof heart failure patients and reduce the burden on the medical system.These new therapies should preferably not require a major surgery,prolonged stay in the hospital or frequent visits to the doctor'soffice.

Hypertension

It is generally accepted that high blood pressure (HBP, also calledhypertension) is bad, but most people don't know why, and what the termreally means. In fact, all humans have high blood pressure some of thetime, and would not be able to function if without periodichypertension, such as during exercise. High blood pressure is of concernwhen it persists for long periods of time or is extremely high over avery short (hours) period of time. The adverse effects of HBP usuallytake many years to develop. But, clinically important HBP is common.According to official government figures, 50 million people in theUnited States suffer from unhealthy HBP.

While everyone has high blood pressure some of the time, many peoplelive their entire lives with moderately high blood pressure and neverknow it until it is notice on a routine visit to the doctor.Unfortunately, not all people are so lucky. In these people, high bloodpressure significantly increases the risk of a number of serious events,mainly strokes and heart attacks.

More specifically, the damage caused by high blood pressure is of threegeneral sorts. The first is the one everyone thinks of—bursting a bloodvessel. While this is dramatic and disastrous when it happens, it'sactually the least common of the three problems. It occurs mostfrequently in the blood vessels of the brain, where the smaller arteriesmay develop a weak spot, called an aneurysm. This is an area where thewall is thinner than normal and a bulge develops. When there is a suddensurge of pressure the aneurysm may burst, resulting in bleeding into thetissues. If this occurs in the brain, it is a stroke. In contrast, if ananeurysm occurs in the aorta (the main blood vessel in the body is aruptured aortic aneurysm. Both of these events can lead to permanentdamage and death.

The second adverse consequence of high blood pressure is that itaccelerates the deposition of cholesterol in the arteries forming ablockage. This problem takes many years to develop and it is difficultto detect, at least until it causes a major blockage. The most importantsites in the human body to be affected by cholesterol blockage are theheart, where the blockage can cause angina and heart attacks; the brain,where it causes strokes; the kidneys, where it causes renal failure (andcan also make the blood pressure go even higher); and the legs, where itcauses a condition known as intermittent claudication, which means painduring walking and may even lead to losing a limb.

Third, high blood pressure puts a strain on the heart. Because it has towork harder than normal to pump blood against a higher pressure, theheart muscle enlarges, just as any other muscle does when it is usedexcessively.

Over a long period of time, high blood pressure can lead to congestiveheart failure, the most frequent cause for hospitalization in the UnitedStates. When the blood pressure reaches a certain high pressure levelfor a sufficient length of time it sets off a vicious cycle of damage tothe heart, brain, and kidneys, resulting in further elevation of thepressure.

Classification of hypertension by its severity is somewhat arbitrarybecause there is no precise level of blood pressure above which itsuddenly becomes dangerous. Historically, blood pressure has beenprimarily classified according to diastolic pressure. Someone whosediastolic pressure runs between 90 and 95 mm Hg may be regarded ashaving borderline hypertension, and diastolic pressure between 95 and110 mm Hg is considered moderate, and at higher levels diastolicpressure is severe.

Recent data suggests that the systolic pressure is as effective as, andmaybe more effective than, diastolic blood pressure in determining thepatient's risk for serious adverse events. Systolic hypertension ismainly seen in people over the age of 65 and is characterized by a highsystolic, but normal diastolic, pressure (a reading of 170/80 mm Hgwould be typical). Systolic hypertension is typically caused by anage-related loss of elasticity of the major arteries.

Another form of HBP is referred to as Labile hypertension, which is acommonly used term for describing people whose blood pressure isunusually labile or variable. The most dangerous type of HBP ismalignant hypertension or high blood pressure with evidence on physicalexam that this pressure is causing an acute deleterious affecting onvital organ function. Malignant hypertension is regarded as an emergencyrequiring immediate treatment in a hospital. If untreated, malignanthypertension can be rapidly fatal. Although more people are treated withdrugs nowadays than before, malignant hypertension is still common.

The objective of HBP treatment is not simply to lower the bloodpressure, but to prevent its consequences, such as strokes and heartattacks. According to the American Heart Association high blood pressureis present in 50,000,000 Americans (Defined as systolic pressure 140 mmHg or greater, and/or diastolic pressure 90 mm Hg or greater, or takingantihypertensive medication). Of those with HBP, 31.6 percent areunaware they have it; 27.4 percent are on medication and have itcontrolled; 26.2 percent are on medication but don't have their HBPunder control; and 14.8 percent aren't on medication. In most cases,high blood pressure can be controlled with one or a combination of oraldrugs. Of those patients that take medication to control HBP, manysuffer from debilitating side effects of these drugs such as heartarrhythmias, inability to exercise or do normal activities of dailyliving and impotence.

Electric Activity of the Heart

In a given cardiac cycle (corresponding to one “beat” of the heart), thetwo atria contract to force the blood therein into the ventricles. Ashort time later, the two ventricles contract, forcing the blood thereinto the lungs (from the right ventricle) or through the body (from theleft ventricle). Meanwhile, blood from the body refills the right atriumand blood from the lungs refills the left atrium, waiting for the nextcycle to begin. A healthy adult human heart may beat at a rate of 60-80beats per minute (bpm) while at rest, and may increase its rate to140-180 bpm when the adult is engaging in strenuous physical exercise,or undergoing other physiologic stress.

The healthy heart controls its rhythm from its sinoatrial (SA) node,located in the upper portion of the right atrium. The SA node generatesan electrical impulse at a rate commonly referred to as the “sinus” or“intrinsic” rate. This impulse is delivered from the SA node to theatrial tissue when the atria are intended to contract. The electricalsignal continues to propagate from the atrial tissue through theatrioventricular (AV) node, a specialized collection of tissue thatserves as a “gatekeeper” for the impulses traveling between the atriaand the ventricles. After a suitable delay (on the order of 140-220milliseconds), the signal finally propagates to the ventricular tissueand the ventricles are stimulated to contract. SA node is the naturalpacemaker of the heart. If it is disabled, there are other specializedareas of the heart muscle that can generate an intrinsic heart rate.

The ventricular muscle tissue in the heart is much more massive than theatrial muscle tissue. The atrial muscle tissue need only produce acontraction sufficient to move the blood a very short distance from therespective atrium to its corresponding ventricle. The ventricular muscletissue, on the other hand, must produce a contraction sufficient to pushthe blood through the complete circulatory system of the entire body.Even though total loss of atrial contraction can lead to a smallreduction of cardiac output it is not an immediate risk to life.Conversely, the atria of the heart can sustain a higher number ofcontractions per minute than the ventricles without endangering life.

Electronic Cardiac Pacemakers

An electronic pacemaker (pacemaker) provides electrical stimulationpulses to the appropriate chamber(s) of the heart (atrium, ventricle, orboth) in the event the heart is unable to beat on its own, e.g., in theevent either the SA node fails to generate its own natural stimulationpulses at an appropriate sinus rate or in the event such naturalstimulation pulses do not effectively propagate to the appropriatecardiac tissue. Most modern pacemakers accomplish this function byoperating in a “demand” mode where stimulation pulses from the pacemakerare provided to the heart only when it is not beating on its own, assensed by monitoring the appropriate chamber of the heart for theoccurrence of a P-wave or an R-wave. If a P-wave or an R-wave is notsensed by the pacemaker within a prescribed period of time (which periodof time is often referred to as the “escape interval”), then astimulation pulse is generated at the conclusion of this prescribedperiod of time and delivered to the appropriate heart chamber via apacemaker lead. Pacemaker leads are isolated wires (called leads)equipped with sensing and stimulating electrodes.

Modern programmable pacemakers are generally of two types: (1)single-chamber pacemakers, and (2) dual-chamber pacemakers. In asingle-chamber pacemaker, the pacemaker provides stimulation pulses to,and senses cardiac activity within, a single-chamber of the heart (e.g.,either the right ventricle or the right atrium). In a dual-chamberpacemaker, the pacemaker provides stimulation pulses to, and sensescardiac activity within, two chambers of the heart, e.g., both the rightatrium and the right ventricle. The left atrium and left ventricle ofthe heart can also be paced, provided that suitable electrical contactsare made therewith.

Much has been written and described about the various types ofpacemakers and the advantages and disadvantages of each. For example,U.S. Pat. No. 4,712,555 of Thornander et al. and U.S. Pat. No. 5,601,613of Florio et al. present background information about pacemakers and themanner in which they interface with a patient's heart.

One of the most versatile programmable pacemakers available today is theDDDR pacemaker. This pacemaker represents a fully automatic pacemakerwhich is capable of sensing and pacing in both the atrium and theventricle, and is also capable of adjusting the pacing rate based on oneor more physiological factors, such as the patient's activity level. Itis commonly accepted that the DDDR pacemaker is superior in that it canmaintain AV synchrony while providing bradycardia (slow heart beat)support. It is also generally more expensive than other, simpler typesof pacemakers. A description of DDDR pacing is included in thisdisclosure as a state of the art.

In general, DDDR pacing has four functional states: (1) P-wave sensing,ventricular pacing (PV); (2) atrial pacing, ventricular pacing (AV); (3)P-wave sensing, R-wave sensing (PR); and (4) atrial pacing, R-wavesensing (AR).

It is accepted as important and advantageous, for the patient withcomplete or partial heart block, that the PV state of the DDDR pacemakertracks the atrial rate, which is set by the heart's SA node, and thenpaces in the ventricle at a rate that follows this atrial rate. It isassumed that because the rate set by the SA node represents the rate atwhich the heart should beat in order to meet the physiologic demands ofthe body (at least for a heart having a properly functioning SA node)the rate maintained in the ventricle by such a pacemaker is trulyphysiologic.

In some instances, a given patient may develop dangerously fast atrialrhythms, which result from a pathologic arrhythmia such as apathological tachycardia, fibrillation, or flutter. In these cases, aDDDR pacemaker may pace the ventricle in response to the sensed atrialarrhythmia up to a programmed maximum tracking rate (MTR). The MTRdefines the upper limit for the ventricular rate when the pacemaker istracking the intrinsic atrial rate. As a result, the MTR sets the limitabove which the ventricles cannot be paced, regardless of the intrinsicatrial rate. Thus, the purpose of the MTR is to prevent rapidventricular stimulation, which could occur if the intrinsic atrial ratebecomes very high and the pacemaker attempts to track atrial activitywith 1:1 AV synchrony.

When the intrinsic atrial rate exceeds the MTR the pacemaker mayinitiate one or more upper atrial rate response functions—such asautomatically switching the pacemaker's mode of operation from an atrialtracking mode to a non-atrial rate tracking mode.

The heart's natural response to a very high atrial rate involves anatural phenomenon known as “blocking”—where the AV node attempts tomaintain a form of AV synchrony by “dropping out” occasional ventricularbeats when the high atrial rate exceeds a certain natural thresholdi.e., the refractory period of the heart tissue. The blocking phenomenonis often expressed as a ratio of the atrial beats to the ventricularbeats (e.g. 6:5, 4:3, etc.). Of particular importance is a 2:1 blockcondition where there are two atrial beats for every one ventricularbeat. The 2:1 block condition is a natural response to a very highatrial rate, during which full ventricular rate synchronization (i.e. ata 1:1 ratio) would be dangerous to the patient.

Some known pacemakers emulate this 2:1 condition, by tracking P-waves upto the device's programmed total refractory period (TARP) of the heart.That is, P-waves which fall in the total refractory period are nottracked, and the device is said to have a “2:1 response mode.” Duringthe 2:1 block response mode, the ventricles are paced at a lower ratethan the natural atrial rate, because P-waves occurring soon afterventricular events are ignored for the purposes of calculating theventricular pacing rate. As a result, the 2:1 block response modeprevents the pacemaker from pacing the ventricles at a tachycardia rate.

The 2:1 block response mode is an effective response for dealing withshort incidences of high atrial rates and in preventing occurrence of apacemaker mediated tachycardia resulting from retrograde P-waves.However, the 2:1 block response mode may become uncomfortable for thepatient if it is maintained for an extended period of time due toprogrammed long atrial refractory periods, because the pacing rate willbe ½ of the required physiologic rate.

Many more advanced pacemaker operation modes have been described andsometimes implemented. Some of these modes included sensing abnormallyhigh atrial rates and prevented them from causing rapid ventricularrates. Common to prior pacing no attempt has been made to induce a rapid(faster than normal) atrial rate by pacing or to pace atria at ratehigher than ventricles.

Pacemaker Syndrome

Although pacemakers provide relief from life-threatening arrhythmias andcan improve quality of life significantly, they also can function in anonphysiologic manner, which is accompanied by nontrivial morbidity.Pacemakers functioning in the VVI mode (e.g., a pacing mode in which thenative atrial electrical or contractile states are not sensed andignored by the pacemaker) have been noted to sacrifice the atrialcontribution to ventricular output. In some instances, and because ofthis lack of feedback, the timing of native atrial contraction andpacemaker-induced ventricular contraction is such that the atrialcontraction occurs during ventricular contraction or against closedatrio-ventricular (A-V) valves (Tricuspid and Mitral), producing reverseblood flow and nonphysiologic pressure waves. The A-V valves normallyopen passively whenever the pressure in the atrium exceeds the pressurein the ventricle. The pressure in the ventricles is low duringventricular diastole (or ventricular filling period). In the case ofnon-physiological pacing, the A-V vales are not able to be normallyopened by the pressure in the atrium during atrial contraction as theventricles are in their pumping period (called ventricular systole) andthe pressure in the ventricles significantly exceeds the maximumpossible pressure able to be generated in the atrial muscle contraction.This abnormal, non-physiological relationship of atrial to ventricularcontraction can occur in other pacing modes if a patient's heart tissueis susceptible to allowing abnormal retrograde (e.g., from the ventricleto the atria) conduction of native or pacemaker-induced ventricularelectrical activity.

Pacemaker syndrome was first described as a collection of symptomsassociated with right ventricular pacing. Since its first discovery,there have been many definitions of pacemaker syndrome, and theunderstanding of the cause of pacemaker syndrome is still underinvestigation. In a general sense, pacemaker syndrome can be defined asthe symptoms associated with right ventricular pacing relieved with thereturn of A-V synchrony. Recently, most authors have recognized thatpacemaker syndrome, which initially was described in patients withventricular pacemakers, is related to nonphysiologic timing of atrialand ventricular contractions, which may occur in a variety of pacingmodes. Some have proposed renaming the syndrome “A-V dyssynchronysyndrome,” which more specifically reflects the mechanism responsiblefor symptom production.

The symptoms of pacemaker syndrome included dyspnea (shortness ofbreath) and even syncope (fainting). Syncope is temporary loss ofconsciousness and posture, described as “fainting” or “passing out.”It's usually related to temporary insufficient blood flow to the brain.It's a common problem, accounting for 3 percent of emergency room visitsand 6 percent of hospital admissions. It most often occurs when 1) theblood pressure is too low (hypotension) and/or 2) the heart doesn't pumpa normal supply of blood to the brain.

In pacemaker syndrome patients, syncope occurs secondary to retrograde,ventricular to atrial (V-A) conduction resulting in the contraction ofthe atria against closed A-V valves. One effect of the elevated atrialand venous pressures associated with the contraction against closed A-Vvalves is to cause a vagal afferent response resulting in peripheralvasodilatation leading to a marked lowering of blood pressure (termedhypotension). Syncope is usually associated with systolic blood pressuredeclines of greater than 20 mm Hg that can occur with the onset ofpacing.

Pacemaker syndrome can also lead to decreased cardiac output, withresultant increase in left atrial pressure and left ventricular fillingpressure. Not only can this decrease in blood flow lead to syncope, thisincrease in atrial pressure or ventricular filling pressure can alsoresult in increased production of atrial natriuretic peptide (ANP) andB-type natriuretic peptide (BNP). ANP and BNP are potent atrial andvenous vasodilators that can override carotid and aortic baroreceptorreflexes attempting to compensate for decreased blood pressure. Patientswith pacemaker syndrome exhibit increased plasma levels of ANP, andpatients with so called atrial pressure “cannon a waves” (cause byatrial contraction against a closed valve) have higher plasma levels ofANP than those without “cannon a waves.”

Natriuretic Peptides (ANP and BNP)

Atrial natriuretic peptide (ANP) is a hormone that is released frommyocardial cells in the atria and in some cases the ventricles inresponse to volume expansion and increased wall stress. Brainnatriuretic peptide (BNP) is a natriuretic hormone that is similar toANP. It was initially identified in the brain but is also present in theheart, particularly the ventricles.

The release of both ANP and BNP is increased in heart failure (CHF), asventricular muscle cells are recruited to secrete both ANP and BNP inresponse to the high ventricular filling pressures. The blood plasmaconcentrations of both hormones are increased in patients withasymptomatic and symptomatic left ventricular dysfunction, permittingtheir use in diagnosis. A Johnson and Johnson Company, Scios sells apopular intravenous (IV) medication Natrecor (nesiritide), a recombinantform of the endogenous human peptide for the treatment of decompensatedCHF. The advent of Natrecor marked an important evolution in theunderstanding and treatment of acute heart failure.

Both ANP and BNP have diuretic, natriuretic, and hypotensive effects.They also inhibit the renin-angiotensin system, endothelin secretion,and systemic and renal sympathetic activity. Among patients with CHF,increased secretion of ANP and BNP may partially counteract the effectsof norepinephrine, endothelin, and angiotensin II, limiting the degreeof vasoconstriction and sodium retention. BNP may also protect againstcollagen accumulation and the pathologic remodeling that contributes toprogressive CHF.

It is well established in scientific literature that infusion of ANPbenefits patients with hypertension. Unfortunately, until now thisknowledge had no practical applications since, due to its biochemicalnature, ANP cannot be produced in a form of oral medication (a pill).There is therefore a need to develop novel ways to deliver ANP topatients who can benefit from it. Inventors propose to stimulate heartatria with an artificial implanted device to cause increased secretionof endogenous ANP.

SUMMARY

The inventors identified in this application observed that—while clearlydeleterious to the majority of heart disease patients—the phenomenon ofthe reduction of blood pressure in response to nonphysiologic pacing canbe beneficial by reducing blood pressure in the group of patients withsevere hypertension and particularly ones with malignant drug refractoryhypertension that frequently results in strokes and sudden death.

The inventors disclosed in co-pending applications a pacemaker that iscounterintuitively used dissynchronously to generate different atrialand ventricular contraction rates. Specifically, a higher rate of atrialcontractions than ventricular contractions is generated. It isunderstood that this may result in suboptimal performance of the heart.However, the inventors propose that this disadvantage of lower bloodpressure from the reflex vasodilation and ANP secretion caused bynonphysiologic pacing can paradoxically benefit some hypertensive andheart failure patients if the increased ANP-BNP secretion from increasedatrial pressures sufficiently increases the release of ANP and BNPhormones to a level that overcomes potential detriments from reducedatrial contribution to cardiac output.

One Embodiment, AV Blocked Electric Stimulation of the Heart

One embodiment disclosed here uses a modified implanted electroniccardiac pacemaker to increase ANP and BNP secretion by pacing the rightatrium of the patient at an appropriately high rate. In the firstdescribed embodiment, patients have either a natural atrioventricularblock (AV block) or have an AV block induced by heart tissue ablation orsome other appropriate procedure. For example in patients with aso-called third-degree AV block (complete AV block, no AV conduction),no atrial impulses reach the ventricles, and ventricular rhythm ismaintained by a subsidiary natural pacemaker. Since subsidiarypacemakers must be below the level of block, their location is in partdetermined by the site of block. In third-degree AV nodal block, theventricular rhythm is usually maintained by pacemakers in the AVjunction with resultant narrow QRS complexes. In third-degree AV blocklocalized to the bundle branches, ventricular rhythm is maintained by apacemaker in the Purkinje fibers, with resultant wide QRS complexes. Thejunctional pacemaker rate is usually faster (40-80 beats/min) comparedwith the peripheral Purkinje network (20-40 beats/min). In suchpatients, a dual chamber pacemaker can be used to pace atria at a ratemuch higher than the ventricles without the risk of patient developingdangerous ventricular tachycardia (rapid heart beat) as the atrialimpulses, either native or pacemaker-induced, are not conducted to theventricle. An atrioventricular (AV) node ablation is a known medicalprocedure that destroys a part of the heart's normal electrical system.The combination of pacing and AV node ablation is sometimes usedclinically in patients with chronic atrial fibrillation and rapidventricular response that poorly respond to drug therapy.

This is accomplished by cauterizing the AV node, which is locatedbetween the upper heart chamber (atria) and the lower heart chambers(ventricles). Once the AV node is cauterized, none or few impulses fromthe atria will be able to reach the ventricles. Currently, an AV nodeablation is performed when the patient's rhythm disturbance (arrhythmia)originates in the atria and its effects on atrial or ventricularfunction cannot be controlled adequately with other measures. Apermanent pacemaker is installed afterwards, to keep the heart beatingat a normal rate. In this case, at least one pacemaker lead is connecteddirectly to a ventricle.

Another Embodiment, Refractory Period Electric Stimulation of the Heart

Inventors realized that it is desired to implement nonphysiologic pacingwith the purpose of increasing atrial wall stress and cause hormonalrelease and vasodilation without blocking natural AV conduction.Inventors discovered that such pacing modality is possible utilizingnaturally occurring periods in the electric cyclic activity of the heartwhen the heart muscle conduction is blocked by so called refractoryperiods.

In the heart are specialized tissue collections that have a uniqueproperty, they rhythmically emit electrical impulses. The cause of thesephenomena is the “leaky membrane that allows the regular exchange ofSodium, Potassium, and Calcium ions and causes a change in thepolarization of the cells. Sodium ions move into the cell and start thedepolarization, Calcium ions extend that depolarization. When theCalcium ions stop entering the cell Potassium ions move in and therepolarization of the cell begins. To simplify this, the Sodium startsthe cells stimulation, the Calcium extends that stimulation to allow theentire muscle to contract before Potassium comes along and tells it torelax for a moment and get ready for the next wave. A material aspect ofthe repolarization—depolarization cycle of the individual heart muscleelements is the “refractory” period where the cells reset for the nextwave and temporarily cannot be electrically stimulated to contract orconduct.

These atrial, AV node and ventricular refractory periods have twostages, the Absolute and Relative refractory periods. In the Absoluterefractory phase, the conduction system and heart muscle are in a“drained” state and need a moment to “recharge” to be able toelectrically and/or mechanically respond to another electrical stimulus.Thus, a pacemaker impulse applied to these structure during this timewould not be electrically conducted or cause the heart muscle tocontract. In the relative refractory period that follows the absoluterefractory period, the electrical conducting tissues and/or heart musclecells are not fully “recharged” but may conduct and/or contract ifexcited with a strong pacing signal.

The refractory period of the atria in the naturally beating heart beginsand ends before the end of the absolute refractory period of theventricle. Therefore, it is possible to generate an electrical stimulusto pace the atria of the heart during the ventricular refractory periodand generate the atrial contraction in such way that this electricalstimulus will not propagate through the AV node to the ventricle andcause a ventricular contraction.

To maximize the affect of the atrial contraction in the terms of maximumatrial muscle wall stress and the subsequent neural activation andhormonal release, it is desired to cause a contraction of the atriumwhen the atrium is filled with blood and its walls are distended. It isalso desired to cause atrial contraction against the closed AV valve,causing the phenomenon somewhat similar to the pacemaker syndrome. Thismaximum stress in the atrial wall caused by the atrial contraction canbe expected to result in the maximum vasodilatation of peripheral bloodvessels that will achieve the desired reduction of systemic atrial bloodpressure.

The atria of the heart naturally contract during the approximately 100ms following the P-wave of the surface ECG of the heart. It isunderstood that for an implanted pacemaker internal electrograms fromdifferent heart chambers are available. It is therefore understood thatreferences to surface ECG in regard to heart cycle timing are made forillustration and the corresponding electrical events can be easilydetected using standard atrial and ventricular electrograms. The Q-waveof the surface ECG corresponds to the beginning of the absoluterefractory period of the atria. The atria passively fill with bloodduring the ventricular systole, which occurs following the Q-wave of thesurface ECG. Approximately half-way or between 100 to 150 ms into theventricular systole period, the atria are fully expanded and primed withblood and the window of opportunity for the maximum benefit fromnonphysiologic atrial pacing begins. The ventricles contract during theventricular systole of the heart and are absolutely refractory toelectric stimulation during this period. Importantly, the atrialrefractory period ends before the 50% of the ventricular systole haselapsed. The atria are now electrically and mechanically “armed” and canbe triggered to contract by a pacing impulse. This window of opportunitycan be defined as occurring from the end of the atrial refractory period(approximately 30 to 50% into the ventricular systole following the Qwave) and the end of the ventricular refractory period that correspondsto the middle of the T-wave, which is also the time when the aorticvalve opens. During this time window, it is possible to apply a pacingsignal to the atrium of the heart, generate a nonphysiologic atrialcontraction without provoking the undesired nonphysiologic ventricularcontraction. The timing diagram on the FIG. 5 of this applicationillustrates the principal of nonphysiologic atrial contraction.

In summary, the following exemplary novel algorithm has been developedto allow a pacemaker stimulated atrial contraction in an intactnaturally beating heart:

A. The end of atrial refractory period is detected or predicted, basedon physiologic monitoring of the heart, for example by detectingsuitable event points of the patient's surface ECG or intracardiacatrial and ventricular electrograms. The end of atrial refractory periodalso corresponds to the end of the depolarization and mechanicalcontractile activity of the atrial heart muscle.

B. The atrium is paced to contract following the end of the refractoryperiod of the atrium but before the end of the refractory period of theventricle, for example in the middle of ventricular systole.

C. In one proposed embodiment, the resulting contraction of the atriumoccurs in the later part of the ventricular systole when atrium isdistended by passive filling with blood. A non-physiological, pacedatrium contraction is then caused during this period which causes theatrium to contract against the closed AV valve, increasing atrialpressure and wall stress leading to beneficial neural and hormonalstimuli. These stimuli are expected to result in 1) peripheralvasodilatation and reduction of blood pressure in hypertensive patientsor 2) increased ANP/BNP secretion leading to beneficial physiologicaland clinical sequelae in patients with CHF.

In one embodiment, a sensing and pacing lead of a pacemaker (implantableor temporary) is placed in an atrium (such as RA) of the heart. Theintracardiac ECG (electrogram) is sensed for signs of atrial andventricular depolarization and repolarization. The beginning and end ofthe atrial refractory period is predicted following a known delay afterthe P wave or R wave of the heart. For example, the atrium can be paced150 milliseconds (ms) after the detected R wave. The desired delay canbe recalculated by the embedded software based on the heart rate or setby the physician during the office visit of the patient. All modernpacemakers include suitable sensing, programmability and telemetryfunctions.

It is understood that there are many ways to detect various phases ofthe electric heart activity cycle using surface or intracardiac ECG,pressures, wall motion or heart sound sensors. It is imagined that someof these signals can be used to synchronize the proposed nonphysiologicpacing to the desired window of the heart cycle. Common to all of thesepotential embodiments, the heart atrium (right or left or both) is pacedafter the end of the atrial refractory period and before the end of theventricular refractory period.

In this embodiment, a pacemaker is counter intuitively useddissynchronously to generate different atrial and ventricularcontraction rates. Specifically, a higher rate of atrial contractionsthan ventricular contractions is generated. It is understood that thismay result in suboptimal performance of the heart. The inventors proposethat this disadvantage will be offset by the benefit of the increasedbeneficial vasodilatory stimulus and hormonal secretion by the heartatria in hypertensive and heart failure patients.

Electronic pacemakers are currently used to replace or supplement thenatural pacing nodes of the heart by applying electric excitory signalsto the heart muscle to cause contraction and blood pumping cycle.Pacemakers are used in patients with diseased nodes (slow heart beat)and defective (blocked) conduction pathways. Bi-ventricular pacemakerspace both ventricles of the heart to restore synchrony between theventricles.

Generally, the conventional wisdom of all pacing therapies for the heartdisease is as follows. A human heart consists of four chambers—two atriaand two ventricles. In order for the heart to efficiently perform itsfunction as a pump, the atrial muscles and ventricular muscles shouldcontract in a proper sequence and in a timed relationship, as they do ina healthy heart. Therefore electronic pacemakers are used to restore thenormal heartbeat or to restore synchrony between different chambers ofthe heart. It is understood that the methods and embodiments describedin this patent may be incorporated into existing pacemaker devices, suchas the pacemakers, biventricular pacemakers, or ICDs.

SUMMARY OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 illustrates the electric excitory pathways and chambers of ahuman heart.

FIG. 2 illustrates an embodiment having a two lead pacing system.

FIG. 3 illustrates one sequence of natural and induced stimulationpulses.

FIG. 4 illustrates intermittent asynchronous pacing.

FIG. 5 illustrates timing of the refractory period pacing.

FIG. 6 illustrates an exemplary relationship between electric activityof the heart and an embodiment of a proposed pacing method.

FIG. 7 illustrates an exemplary group of elements of an embodiment ofembedded logic of a pacemaker.

FIG. 8 illustrates an exemplary group of elements of an embodiment ofembedded logic of a pacemaker, primarily related to protecting a patientfrom excessively low heart rate induced by therapy.

FIG. 9 illustrates an embodiment of logic for a more flexible, adaptiveimplementation of therapy.

FIG. 10 illustrates traces from an experiment testing an embodiment of apacing method.

FIG. 11 illustrates traces from another experiment testing anotherembodiment of a pacing method.

DETAILED DESCRIPTION

FIG. 1 shows a normal heart. Electrical pulses in the heart arecontrolled by special groups of cells called nodes. The rhythm of theheart is normally determined by a pacemaker site called the sinoatrial(SA) node 107 located in the posterior wall of the right atrium 102 nearthe superior vena cava (SVC) 101. The SA node consists of specializedcells that undergo spontaneous generation of action potentials at a rateof 100-110 action potentials (“beats”) per minute. This intrinsic rhythmis strongly influenced by autonomic nerves, with the vagus nerve beingdominant over sympathetic influences at rest. This “vagal tone” bringsthe resting heart rate down to 60-80 beats/minute in a healthy person.Sinus rates below this range are termed sinus bradycardia and sinusrates above this range are termed sinus tachycardia.

The sinus rhythm normally controls both atrial and ventricular rhythm.Action potentials generated by the SA 107 node spread throughout theatria, depolarizing this tissue and causing right atrial 102 and leftatrial 106 contractions. The impulse then travels into the ventriclesvia the atrioventricular node (AV node) 108. Specialized conductionpathways that follow the ventricular septum 104 within the ventriclesrapidly conduct the wave of depolarization throughout the right 103 andleft 105 ventricles to elicit the ventricular contraction. Therefore,normal cardiac rhythm is controlled by the pacemaker activity of the SAnode and the delay in the AV node. Abnormal cardiac rhythms may occurwhen the SA node fails to function normally, when other pacemaker sites(e.g., ectopic pacemakers) trigger depolarization, or when normalconduction pathways are not followed.

FIG. 2 shows a heart treated with one embodiment. Pulse generator(pacemaker) 201 is implanted in a tissue pocket in the patient's chestunder the skin. In this embodiment the generator 201 is connected to theheart muscle by two electrode leads. The ventricular lead 202 is incontact with the excitable heart tissue of the right ventricle 103. Theatrial lead 203 is in contact with the excitable heart tissue of theright atrium 102. It is understood that the pacemaker can have moreleads such as a third lead to pace the left ventricle 105. It isexpected that in future cardiac pacemakers will have even more leadsconnecting them to various parts of the anatomy.

Leads 203 and 202 can combine sensing and pacing electrodes as known andcommon in the field. The atrial lead 203 can therefore sense the naturalintrinsic contractions of the atria before they occur and communicatethem to the generator 201. Atrial lead can be also used to implementbackup pacing if the natural heart rate drops below the desired value(for example 50/min) as a result of the therapy. Similarly, ventricularlead 202 can be used for further backup ventricular pacing if atrialpacing was, for some reason, ineffective.

Ventricular lead 202 can be used to sense ventricular depolarization.This is significant since it allows accurate detection of theventricular contraction when ventricle is refractory and A-V valve isclosed. It also can be used to confirm that the therapeutic atrialpacing did not conduct to the ventricle. If conduction to atrium isdetected, the timing of atrial pacing can be adjusted based onventricular electrogram feedback.

Although it is possible to implement the embodiments disclosed hereinusing atrial lead only, ventricular lead adds to the reliability andsafety of the proposed embodiment. The generator is equipped with theprogrammable logic that enables it to sense signals from leads and othersensors, such as motion or physiologic activity sensors, process theinformation, execute algorithms, and send out electric signals to theleads.

In one described embodiment the natural conduction path between the SAnode 107 and the AV node 108 is blocked. The patient may already have anatural complete AV block. In this case no intervention is needed. Ifthe patient has functional electric pathways from atria to ventricles,the patient's AV node can be disabled (blocked) by tissue ablation. Itis understood that many irreversible and reversible methods ofselectively blocking conduction in the heart are known. These includetreatment with chemical agents and blocking with subthreshold electricstimulation (non-excitatory stimulation that does not cause musclefibers to contract). Ablation of the AV node is used as an example sinceit is widely accepted and easily performed using RF energy catheters.Other devices that use cold, laser and ultrasound energy to performablation are also known.

FIG. 3 illustrates sensing and pacing sequences for an embodiment havingsequence of stimulation pulses. Pulses are simplified and presented asrectangular blocks spaced in time as represented by the X-axis.

Trace 301 illustrates the natural or intrinsic rate generated by the SAnode of the heart. The SA node generates atrial polarization pulses 304,305, 306 and 307. These pulses can be sensed by the atrial lead 203.

In response to the sensing of intrinsic atrial pulses, the pulsegenerator 201 generates a series of pulses represented by the trace 302.Pulses are conducted to the atria by the atrial lead 203. Devicegenerated atrial stimulation pulses 311, 313, 315 and 317 are not neededif SA node generated atrial pulses 304, 305, 306 and 307 occur atdesired rate, for example every second or faster. Ventricular pulsescorresponding to naturally occurring atrial pulses 304, 305, 306 and 307represent the intrinsic pumping heart rate. The generator 201 (based onan embedded algorithm) also generates extra atrial pulses 312, 314 and316. Together natural pulses 304, 305, 306 and 307 or pacemakergenerated pulses 311, 313, 315, 317 and asynchronous pulses 312, 314,316 determine the atrial rate of the heart. Pacemaker pulses 311, 313,315 and 317 represent atrial backup rate. They are only needed if nativeatrial pulses 304, 305, 306 and 307 do not occur in time to maintain thedesired pumping heart rate.

Trace 303 represents ventricular stimulation pulses 321, 322, 323 and324 conducted to the ventricle of the heart by the ventricular lead 202.The AV node of the heart in this embodiment is blocked during the entireheart cycle. Therefore the ventricular stimulation is always generatedby the generator 201 based on an embedded algorithm. To ensure betterperformance of the heart ventricular pulses 321, 322, 323 and 324 aresynchronized to the synchronous paced atrial pulses 311, 313, 315 and317 or sensed atrial events 304, 305, 306 and 307 with a short delay 308determined by the embedded algorithm that simulates the natural delay ofthe AV node conduction. Therefore for pumping heart beats, normalsynchrony is maintained.

The algorithm illustrated by the FIG. 3 can be described as a sequenceas follows:

a. sensing an intrinsic SA node generated atrial pulse (P-wave),

b. generating a backup synchronous atrial pacing pulse if intrinsicatrial pulse is not sensed in time,

c. calculating the intrinsic atrial rate based on previous SA node pulseintervals or pacemaker setting by programming and embedded logic,

d. generating synchronous ventricular pacing signal delayed from thesynchronous atrial pacing signal at the ventricular rate equal to theintrinsic SA node excitation rate (sinus rhythm),

d. calculating the desired increased atrial rate, such as for example, a2:1 (A:V) rate,

e. generating asynchronous atrial pacing signal based on the calculatedincreased atrial rate, and

f. waiting for the next intrinsic SA node generated atrial pulse(P-wave).

It is understood that this example of an algorithm is an illustrationand many other embodiments of the algorithms can be proposed. It can beenvisioned that more than 2:1 (atrial:ventricular) rate can be toleratedby the patient or that less than 2:1 rate is desired such asaccelerating every second atrial beat.

In some clinical cases it may be not essential to preserve the naturalsinus rhythm (from the SA node) when possible. In some patients it maybe desired for the algorithm to take over the heart rate and force allthe atrial contractions. Pacing modalities that do not rely on the SAnode to generate the heart rate are known and used to treat bradycardia.The SA node of a patient can be ablated similar to the AV node and theembedded pacemaker algorithm will pace the atria. Alternatively, atriamay be paced if the natural SA node pulse is not senses within theexpected time from the last ventricular contraction. Various activitysensors such as accelerometers can be used to accelerate the heart rateas needed.

FIG. 4 illustrates an intermittent application of the proposed therapy.It is possible that some patients will not need or will not be able totolerate continuous asynchronous A-V (atria-ventricular) pacing. In suchpatient period of normal (synchronous) pacing 401 is followed by theperiod of asynchronous (accelerated atrial) pacing 402 followed again bythe period of synchronous pacing 403. The ventricular pacing rate 405 inthis example stays the same. Switching between rates can be based ontiming, patient's activity, or physiologic feedbacks. For example, thepattern of therapy using electrical stimuli to generate high atrialrates can be intermittent of varying duration of accelerated atrialpacing in intervals of 10-60 minute durations occurring, for example, 3times per day. Alternatively asynchronous pacing periods 402 can beautomatically, repeatedly and selectively applied when patient is atrest (for example as detected by a pacemaker motion sensor) or asleep.

Commonly, in comparison to previous devices, this embodimentpurposefully creates ratios of atrial to ventricular contraction higherthan 1:1, such as for example in the range of 1:1 to 4:1. In addition,any previous device that allowed more that a 1:1 ratio of contractionbased this relationship on sensing native atrial depolarization anddeferring generation of a ventricular pacing stimulus (skippingpremature ventricular beats). In contrast, in the illustratedembodiment, the higher than 1:1 rate is intentionally and controllablyinitiated by the implantable generator. As a result the atrial rate isincreased to a rate which causes the release of sufficient endogenousnaturetic hormone to result in a therapeutically beneficial increase inblood plasma levels of the hormones or increased levels in any othervascular or non-vascular space in which these hormones a found.

It is desirable to cause a therapeutic increase of blood plasma ANP andBNP via an increased endogenous release of ANP and BNP from the atria ofthe patient's heart. Atrial release is mediated via increase of atrialwall stress. A preferred embodiment includes rapid pacing of the atriathat is expected to increase the rate of contractions of the atria andrelease ANP and BNP. The embodiment has been described in connectionwith the best mode now known to the applicant inventors.

FIG. 5 illustrates the different, more sophisticated embodiment of thealgorithm for refractory period atrial pacing of the heart. The heart(See FIG. 1) has intact electric conduction including substantiallynormal physiologic intact A-V node conduction delay. Pacing in thisembodiment is implemented by electric stimulation with an atrial lead203 (See FIG. 2). Sensing of electric activity can be performed with theatrial lead 203 or ventricular lead 202 or both. Although it is possibleto infer all electric events in the heart needed to implement thetherapy from atrial electrogram only, sensing both atrial andventricular electric activity is likely to ensure the most reliable andprecise operation of the device. When the patient ECG is discussed it isunderstood that the corresponding events can be reliably sensed in wellknown way by intracardiac leads.

Natural pacemaker or SA node of the heart initiates the Heart cycle withthe P wave 501 of the ECG that corresponds to the atrial depolarizationand the beginning of atrial contraction. It is also the beginning of theheart systole. Atrial pressure 502 increases and atrial volume 503decreases. This time corresponds to the beginning of the atrialrefractory period 508. During this period atria can not be paced tocontract.

The P wave of the ECG is followed by the Q wave 505 that signifies thebeginning of the isovolumic contraction of the ventricle. Ventricularpressure 504 rise begins rapidly. In response the Tricuspid and Mitralvalves of the heart close. Ventricular refractory period 510 begins. Atthe end of isovolumic contraction 509 Pulmonary and Aortic valves openand the ejection of blood from the ventricle begins. Ventricularpressure reaches its peak in the middle of systole 519. Atrium ispassively filled with blood as it relaxes 513. Approximately by themiddle of systole both heart atria are filled with blood 511 and theirrefractory period is over. Atria are primed for a new contraction whilethe ventricle is ejecting blood. A-V valves are closed. At the same timethe ventricle is still refractory and will not start another contractionin response to a natural or artificial pacing stimulus. Heart waves Q505, R 506 and S 507 are commonly used markers of the beginning of theisovolumic contraction and the beginning of ventricular ejection (Swave). Modern pacemakers are equipped with means to read and analyze theelectric activity of heart chambers that are suitable for thisembodiment.

Systole ends when the aortic valve closes 512. Isovolumic relaxation ofthe ventricle starts. This point also corresponds to the middle of the Twave 514 of the ECG. The middle of T wave 514 corresponds to the end ofthe absolute refractory period of the ventricle. At the end of theT-wave Tricuspid and Mitral valves open and the atrium volume starts todrop 520 as the blood starts to flow from the atria into ventricles toprime them for the next ventricular contraction and ejection.

For this embodiment, the window of pacing opportunity 515 starts afterthe end of the atrial refractory period 508 and preferably but notexclusively after the atrium is filled with blood 511 and extended.During this window the atrium is primed and can be paced with apacemaker pulse 516 that can occur at approximately the middle ofsystole or approximately 100-150 ms following the detected R wave 506. Rwave can be sensed as ventricular polarization voltage by theventricular lead 202 (See FIG. 2) It can also occur approximately 300 msafter P wave 501 is detected by the atrial lead. Both P-wave and R-wavecan be used by themselves or in combination to trigger pacing 516. Inresponse to pacing 516 atrium contracts generating a pressure rise 517that results in the desired increased stress of the atrial wall muscle,release of atrial hormones and neurologic activation. Significantly thewindow 515 overlaps the ventricular refractory period 510. Pacing atriaoutside of that time period is not desired since it can cause anarrhythmia and a premature ventricular beat. It is anticipated thatadjustments to timing will be needed if such pacing outside of theventricular refractory period is detected as can be indicated by thepresence of A-V conduction on electrograms (such as a Q wave follows a Pwave).

As a result of the proposed therapy embodiment heart atria should beatat the rate 2:1 in relation to the heart ventricles. First physiologicatrial contraction 502 will be initiated by the natural pacemaker of theheart. Second non-physiologic atrial contraction 517 will occur duringthe heart systole, when the ventricle and/or AV node is refractory tostimulation. It may not be necessary to pace during every natural heartbeat. Pacing can be applied only during part of the day or every secondor third beat to give heart the needed rest and prevent of delaypotential chronic dilation of the double-paced atria and potential heartfailure.

FIG. 6 further illustrates a relationship between the electric activityof the heart and the proposed novel pacing method. Atrial refractoryperiod corresponds to the depolarization of cells in the atrium muscle601. Ventricular refractory period corresponds to the depolarization ofcells in the muscle of the ventricle 510. Pacing 516 generates secondatrial contraction during the window 515. Appropriate trigger pointssuch as P-Q-R-S waves of the ECG 603 can be used by the embeddedpacemaker software to generate the pacing spike 516 after an appropriatedelay has elapsed from the selected P or R wave or both. This delay canbe adjusted by the physician by reprogramming the pacemaker orautomatically corrected based on the patient's heart rate and/or sensedlevel of physical activity. In most general terms pacing should occurafter the R wave and before the T wave of the ECG 603. A delay ofapproximately 100-150 ms can be implemented after the R wave to allowatria to safely exit the relative refractory period and to allow atriato distend and fill with blood.

A preferred embodiment of the disclosed algorithm for a pacemakerstimulated atrial contraction in an intact naturally beating heartduring ventricular refractory period may include the followingadditional steps:

A. Backup pacing to maintain pumping heart rate above certain value.This value can be constant or change based on physical activity.

B. Monitoring of physical activity to turn pacing on only when patientis at rest or adjusting pacing parameters based on activity.

C. Methods of automatically adjusting the timing of pacing. The goal ofadjustments is to accommodate possible changes of the length ofventricular or AV node refractory period.

For the purpose of this disclosure ventricular refractory period relatesthe refractory state of the ventricle or the AV node for as long as theatrial natural or paced electric stimulation is blocked from propagatingto the ventricle and causing a mechanical contraction of a ventricle.

In the embodiment disclosed herein, the therapy is implemented by analgorithm embedded in the implantable pacemaker that is equipped with anatrial lead and a ventricular lead. Both leads are equipped withelectrodes capable of pacing appropriate chambers of the heart andsensing electric activity of these chambers, such as depolarization andaction potentials.

It is a well known fact in the field of electrophysiology of the heartthat if the heart's atrium is paced resulting in atrial contraction, theSA node (the natural pacemaker of the heart) becomes depolarized and thecyclical timing of the SA node becomes reset. This resetting of the SAnode manifests as a delay of the next heartbeat originated by the nextspontaneous SA node generated action potential. If the heart is beatingnaturally, following the periodic SA node cycling, inserting an AC meansthat the heart rate (HR) will be reduced.

When the heart rate or HR is discussed, it relates to the rate ofventricular contractions expressed in beats per minute (/min). It issometimes called “pumping rate” for clarity. The time period separatingtwo ventricular contractions (natural or paced) is called R-R intervaland is expressed in milliseconds or ms. The HR is therefore equal to60,000 ms divided by R-R interval.

It is understood that the HR can be reduced by the resetting of the SAnode by the paced AC as described herein. It is also understood that theHR can be increased by atrial pacing or ventricular pacing at a ratethat is faster than the native SA node rate or the reset (slowed down)SA node rate. Therefore the potentially excessive reduction of the HR bythe invented method can be easily mitigated by backup pacing.

The aspects of the embodiments disclosed herein further are related tothe effect of the proposed therapy on the heart rate. It is wellrecognized by cardiologists that appropriate reduction of the HR can beof some benefit to the patient in some cases. At the same time, if theHR becomes too low, below some individual level for the particularpatient that can be determined clinically, the patient's blood pressurecan become dangerously low. For example, a patient can be tested by aclinician prior to therapy. It could be found that the reduction ofheart rate from 75 to 60/min was beneficial and tolerated, but thereduction of HR to or below 50/min resulted in hypotension. Parametersthus established can become programmed limits for the pacemaker logic.After the patient has lived with the pacemaker for some time, patientcan be retested and the parameters can be adjusted. It is common toprogram and reprogram pacemakers using telemetry. The technology forprogramming exists and is well understood by pacemaker manufacturers andusers. The specific programmable parameters of the proposed novelpacemaker logic are discussed below.

In the disclosed embodiments the AC is induced by the artificial atrialelectric pacing pulse further called A2. A2 is issued by the pacemakerusing the atrial lead after a delay, further called T1, and following anatural or paced atrial action potential further called A1. The A1causes atrial contraction that is conducted to the ventricle and resultsin a ventricular contraction while A2 preferably does not unless it isintended to determine the length of ventricular refractory period.Different from A1 and to be effective, the A2 causes only atrialcontraction that is not conducted to the ventricle. This is achievedprimarily by the delay, further called T1, between A1 and A2 that isimplemented by the pacemaker embedded electronics logic.

The pacemaker is also equipped with means to verify that the A1 and A2events occur as desired. The most reliable method of verification is toacquire electrograms from both atrial and ventricular leads. Followingan A1 there shall be a ventricular action potential, following an A2there should be none. It is also possible to implement verificationusing only the atrial lead by sensing far field ventricular electricwaves in the atrium. Such method of sensing ventricular electric signalsin the atrium is known, but is considered less reliable. At the sametime there is some advantage to having a pacemaker with only one atriallead.

As we discussed above, to safely insert an AC as a part of long termchronic therapy, requires real-time monitoring and analysis of atrialand ventricular electrograms. In the medical practice it is expectedthat some patients will have abnormal electric conduction in the heartsuch as increased A-V delay, heart blocks of various degrees andpremature atrial and ventricular contractions (PACs and PVCs). Inaddition to monitoring it is proposed to implement backup safety pacingto avoid risk.

As was disclosed previously there is a finite window of opportunity forAC insertion. Based on the experiments by inventors, it is likely morethan 150-175 ms and less than or close to 300 ms on following thenatural or paced atrial contraction A1 that propagated to the ventricleand generated a heartbeat. These limits, as well as the time needed forthe SA node to recover, may vary from patient to patient and within thesame patient depending on patient's activity, change of health, andother intrinsic and extrinsic factors. Therefore there is a need forembedded logic in the pacemaker that would have parameters settable byclinician and likely change the timing of pacing as needed based onphysiologic feedbacks.

It is generally desired for the disclosed embodiments, to introducepaced AC towards the end, but not after the end, of the ventricularrefractory period. Since the refractory period can change, method isproposed for dynamically adjusting the timing of pacing. In addition topassive adjustment based on continuous monitoring of atrial andventricular electrograms active experiments can be automaticallyconducted by the embedded logic of the pacemaker. For the purpose ofestablishing the refractory period T1 can be gradually increased anddecreased from heart beat to heart beat, by for example a 10 ms or othersmall time increment. Gradual increase of T1 will at some point resultin the propagation of contraction from atrium to the ventricle, whichcan be detected. The embedded logic can use value T1 that is somewhatless (for example by 30 ms) than thus experimentally establishedventricular refractory period. It can be envisioned that a skilledpacemaker designer can implement other real time algorithms to enableinsertion of PACs at the time close to the end of the ventricularrefractory period.

FIG. 7 illustrates one group of elements of the embedded logic.Pacemaker logic senses 701 the A1 event that can be: spontaneous atrialaction potential sensed by atrial lead, spontaneous ventricular actionpotential sensed by ventricular lead or a paced event applied by atrialor ventricular lead. For certainty, it can be envisioned that acombination of some of this events may be required to identify the eventas a true A1 event. Confirmation of the true A1 event 702 can berequired. For example, if a spontaneous atrial event is sensed, actioncan be delayed until the ventricular action potential is sensed, thisconfirming propagation. If the A1 event is a paced atrial event,confirmation of capture and ventricular contraction can be required toimplement the rest of the therapy algorithm during the same (as sensing701) heart cycle. Alternatively the logic may wait until the next A1event 710.

An important parameter of the proposed therapy is the delay T1 703 thatseparates the sensed A1 event from the AC insertion event 704.

The proposed logic is designed to address issues associated with bothtoo short and too long T1 delays. If the T1 delay is too short, theremay be risk of inducing atrial fibrillation. There is also a functionallimitation to the minimum T1. The atrial tissue is refractory for someamount of time and pacing during that absolute atrial refractory periodwill not cause capture of the atrium and conduction of pacing stimulusthroughout the atrium and back to the SA node. In addition, while the SAnode does not have a refractory period, there is a certain amount oftime during which impulses originating in the atria will not enter theSA node. Thus, if logic paces too early after A1, the A2 pacing stimuluswill not conduct back into the SA node and will not cause resetting ofthe SA node and the atrial contraction.

Logic validates the A2 event 706 by sensing propagation of the heartcycle from the atrium to the ventricular action potential with theventricular lead. If the ventricular action potential propagation occurs706 (indicating contraction) following A2, the delay is likely too long.Logic can reduce the delay 708 by some amount, for example 20 ms, beforethe next heart cycle.

Logic can also test that the electrically paced A2 event actually causedatrial contraction or “capture” 707. If capture did not occur and theatrium did not contract the delay T1 may need to be increased.

It is understood that the elements of logic presented by the FIG. 7 arerelatively independent and can be selectively implemented in apacemaker.

FIG. 8 illustrates another group of elements of the embedded logicprimarily related to protecting the patient from excessively low heartrate induced by therapy.

Execution of this logic can start with the event of a confirmed AC 702(See FIG. 7) that implies that the heart cycle is likely to beprolonged, but counting of the R-R interval 801 starts from the lastconfirmed ventricular contraction. For example, logic can start countingelapsed R-R interval time form last ventricular action potential sensedby the ventricular lead. It is anticipated that the programmability ofthe logic will allow clinician to set maximum allowed R-R interval forthe patient. For example, setting of 1,000 ms will mean that the HR isnot allowed to drop below 60/min without logic taking action. If theobserved time exceeds the limit 802 logic forces a heartbeat to maintainblood pressure.

If next spontaneous atrial A1 event is not identified by the timeallowed, atrium is paced and the A1 event is forced. If patient has aknown A-V conduction block 803, ventricle can be paced instead 806. Ifthe paced A1 event 804 did not result in the successful capture andventricular contraction 805, ventricle can be paced. In any case the newA1 event is generated and the heart rate is maintained by all availablemeans above the clinically acceptable minimum level. This level can bepreset in the embedded logic or adjusted based on the patient's activitylevel.

FIG. 9 illustrates one embodiment of logic for a more flexible, adaptiveimplementation of the therapy. It is known that during exercise humansrely on increased HR to sustain blood pressure and oxygen delivery. Itis desired that the pacemaker does not interfere with physical activity.Logic can rely on known methods such as accelerometers to detect motionto identify activity 900. In addition, patient's breathing can be sensedto automatically initiate and control pacing as needed. Embedded sensorssuch as transthoracic impedance measurement are used in pacemakers tomonitor breathing. Slow, shallow regular breathing is an indication thatthe patient is at rest. Increase of respiration rate and depth indicatesphysical activity. Pacing may be applied when patient is asleep or atrest 901. Motion sensors such as accelerometers can be used to detectthat the patient is resting. Almost all modern pacemakers include atleast one activity sensor, typically an accelerometer. Alternatively theinformation can be derived from the respiration pattern and heart rhythmor a combination of these parameters to increase the certainty ofdetection. In another possible embodiment, patient may turn pacing on,when going to bed to sleep or rest and turn it off when awake or active.Patient may communicate to an implanted device using known methods suchas magnets and magnetic sensors, RF communication and others. As analternative to turning pacing on and off parameters that determinemaximum and minimum allowed heart rate limits can be adjusted. Delay T1can be reduced, when activity is detected and/or maximum allowed R-Rinterval can be made shorter. Other ways of adjusting pacing timingbased on activity are known in the field of demand pacing.

FIG. 10 illustrates an experiment conducted by inventors to test theembodiment in an animal. Traces from the top are: Aortic Blood Pressure1001, Left Ventricular Blood Pressure 1002, Atrial electrogram 1003 andVentricular electrogram 1004. When pacing is ON (left panel) heart rateand blood pressure are reduced. Pacing is applied to the atrium and isindicated by large spikes 1005 on the atrial electrogram 1003. Pacingspike 1005 is delayed by 200 ms from natural atrial depolarization 1006and by 80 ms from natural ventricular depolarization 1007. As desired,atrial pacing 1005 did not propagate to ventricular contraction asevidenced by the ventricular electrogram 1004 and left ventricularpressure trace 1002. Pacing 1005 generated an inserted AC as describedin this application. When pacing is OFF heart rate is between 100-104bpm. When pacing is ON heart rate varies between 60-bpm since it isdetermined by the intrinsic SA node activity.

FIG. 11 illustrates a different experiment conducted by inventors totest the embodiment in an animal to test implementation of backup pacingin addition to AC insertion. Traces from the top are the same as on theFIG. 10: Aortic Blood Pressure 1001, Left Ventricular Blood Pressure1002, Atrial electrogram 1003 and Ventricular electrogram 1004.

Different to FIG. 10 two artificial pacing signals are applied per eachheart beat. Backup pacing pulse 1001 is applied to the atrium outside ofthe refractory period. It propagates to the ventricle and causesventricular depolarization 1102. Pacing pulse 1103 is applied during therefractory period of the ventricle and generates a AC. Pacing 1103 isdelayed by 400 ms from backup pacing 1101 and by 200 ms from atrialdepolarization 1103. It also results in the delay of the natural SA noderhythm and the next heartbeat is initiated by the next pacing spike1004. When pacing is ON (Left Panel) heart rate is exactly 50 bpm anddetermined by backup pacing. When the pacing is turned OFF native heartrate is 80-84 bpm determined by the SA node activity.

FIG. 10 illustrates how in the setting of relatively fast intrinsicheart rate it could be safely reduced just by inserting an AC 200 msafter each atrial depolarization. FIG. 11 illustrates how in the settingof slower intrinsic heart rate backup pacing can be useful to maintainheart rate above minimum allowed value (50 bpm in this case). Bothfigures illustrate how both atrial and ventricular electrograms can beused to time pacing (by counting time delay after easily detectableatrial or ventricular depolarization spike). They also illustrate howthe electrograms can be used to confirm propagation of pacing from theatrium to the ventricle.

A method has been developed of controllably reducing blood pressure in ahuman using an implantable cardiac pacemaker capable of pacing an atriumof a heart comprising: sensing the ventricular refractory period, pacingthe atrium of the heart during ventricular refractory period, with afirst pacing pulse, where said first atrial pacing pulse is blocked anddoes not propagate to the ventricle, where said first atrial pacingpulse further results in atrial contraction against a closed A-V valveand induced increased atrial wall stress resulting in ANP release by thestressed atrial wall; monitoring resulting HR of the patient; applyingsecond pacing pulse to the atrium of the heart if the HR is less thanminimum allowed HR value set by the pacemaker logic.

A method has been developed that controllably reduces blood pressure ina human using an implantable cardiac pacemaker capable of pacing anatrium of a heart comprising: sensing first ventricular contraction ofthe heart, pacing the atrium of the heart after a preset delay followingsaid contraction, during ventricular refractory period, with a firstpacing pulse, where said first atrial pacing pulse is blocked and doesnot propagate to the ventricle; monitoring resulting HR of the patient;and applying second pacing pulse to the atrium of the heart if the HR isless than minimum allowed HR value set by the pacemaker logic.

The method may further comprise steps of reducing said delay time if thesaid first atrial pacing is detected to propagate to the ventricle. Themethod may further comprise the steps of periodically increasing saiddelay to determine the end of ventricular refractory period. The methodmay further comprise setting the time of said second atrial pacing to atime slightly less than the determined refractory period. The method mayfurther comprise suspending therapy if patient's exercise activity isdetected by the pacemaker. The method may further comprise atrial pacingdelivered in response to sensed ventricular depolarization. The methodmay further comprise atrial pacing delivered in response to sensedventricular depolarization after a preset delay from said sensedventricular depolarization. The method may further comprise atrialpacing delivered in response to sensed atrial depolarization. The methodmay further comprise suspending and restarting therapy based on thesensed patient's exercise activity as detected by the pacemaker.

A method has been developed of artificially inducing atrial wall stressto induce a peripheral vascular vasodilation and thereby effect a changein the blood pressure in a patient, the method comprising the steps of:detecting ventricular depolarization; applying atrial pacing to induceatrial contraction, where said pacing is applied when the ventricularpressure is higher than atrial pressure and when the AV conduction isrefractory and said atrial pacing is blocked and does not propagate tothe ventricle; monitoring resulting HR of the patient; and applyingsecond backup pacing to the atrium or ventricle of the heart if the HRis less than minimum allowed HR value set by pacemaker.

A method has been developed of controllably reducing heart rate bypacing a heart of a patient having an atria and a ventricle comprising:sensing first ventricular contraction of the heart; pacing the atrium ofthe heart, where the atrial pacing occurs after the end of the atrialrefractory period, during the ventricular refractory period of the heartand results in an atrial contraction that is not propagated to a secondventricular contraction, where said atrial contraction results invasodilation and ANP release.

The method may further include a step of monitoring of the ventricularcontraction resulting from pacing and adjusting the time of the saidatrial pacing. The method may further include where said pacing occursafter a delay time following said sensed ventricular contraction. Thedelay may be adjusted based on the propagation of the said pacing to theventricle. The method may further including a step of monitoring of aspontaneous heart beat after said pacing and delivering another pacingto the heart if the delay is longer than a preset time, where the presettime corresponds to a lowest selected heart rate and thus applied pacinggenerates ventricular contraction.

The invention has been described in connection with the best mode nowknown to the applicant inventors. The invention is not to be limited tothe disclosed embodiment. Rather, the invention covers all of variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

What is claimed is:
 1. A device for controlling heart contraction toreduce blood pressure, the device comprising: at least one electricallyconductive lead configured to connect to a heart of a patient; anelectrical pulse generator connectable to the at least one electricallyconductive lead and configured to: apply to an atrium of the heart afirst atrial pacing upon expiration of a predetermined delay followingan atrial refractory period of the heart and during a ventricularrefractory period of the heart, monitor a heart rate of the patient inconjunction with applying the first atrial pacing, and apply a secondatrial pacing to the atrium if the monitored heart rate is less than apredetermined minimum heart rate.
 2. The device of claim 1, wherein theelectrical pulse generator is configured to reduce the predetermineddelay in response to a detection of propagation of the first atrialpacing to a ventricle of the heart.
 3. The device of claim 1, whereinthe electrical pulse generator is configured to periodically increasethe predetermined delay to coincide with an expiration of theventricular refractory period.
 4. The device of claim 3, wherein theelectrical pulse generator is configured to set a time of the secondatrial pacing to a time less than the expiration of the ventricularrefractory period.
 5. The device of claim 1, wherein the electric pulsegenerator is configured to suspend application of the first atrialpacing and the second atrial pacing in response to a detected activitylevel of the patient that is above a predetermined threshold level. 6.The device of claim 5, further comprising an activity sensor configuredto detect the activity level of the patient.
 7. The device of claim 1,wherein the electrical pulse generator is configured to apply the firstatrial pacing in response to a sensed ventricular depolarization of theheart.
 8. The device of claim 7, further comprising a sensor configuredto sense the ventricular depolarization of the heart.
 9. The device ofclaim 1, wherein the electrical pulse generator is configured to applythe first atrial pacing upon expiration of a predetermined delay from asensed ventricular depolarization of the heart.
 10. The device of claim9, further comprising a sensor configured to sense the ventriculardepolarization of the heart.
 11. The device of claim 1, wherein theelectrical pulse generator is configured to apply the first atrialpacing based on a sensed atrial depolarization of the heart.
 12. Thedevice of claim 11, further comprising a sensor configured to sense theatrial depolarization of the heart.
 13. The device of claim 1, whereinthe electrical pulse generator is configured to apply the first atrialpacing between approximately 150 milliseconds and 300 milliseconds aftera sensed first ventricular contraction.
 14. The device of claim 13,further comprising a sensor configured to sense the first ventricularcontraction of a ventricle of the heart.
 15. The device of claim 1,wherein the atrium comprises one of a left atrium or a right atrium. 16.The device of claim 1, wherein the predetermined minimum heart rate isless than approximately 50 beats per minute.